Jiang Yanan, Du Weijie, Chu Qun, Qin Ying, Tuguzbaeva Gulnara, Wang Hui, Li Anqi, Li Guiyang, Li Yanyao, Chai Lu, Yue Er, Sun Xi, Wang Zhiguo, Pavlov Valentin, Yang Baofeng, Bai Yunlong
Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.
Cell Physiol Biochem. 2018;45(1):192-202. doi: 10.1159/000486357. Epub 2018 Jan 15.
BACKGROUND/AIMS: Arsenic trioxide (ATO) is a known anti-acute promyelocytic leukemia (APL) reagent, whose clinical applications are limited by its serious cardiac toxicity and fatal adverse effects, such as sudden cardiac death resulting from long QT syndrome (LQTS). The mechanisms of cardiac arrhythmia due to ATO exposure still need to be elucidated. Long non-coding RNAs (lncRNAs) are emerging as major regulators of various pathophysiological processes. This study aimed to explore the involvement of lncRNAs in ATO-induced LQTS in vivo and in vitro.
For in vivo experiments, mice were administered ATO through the tail vein. For in vitro experiments, ATO was added to the culture medium of primary cultured neonatal mouse cardiomyocytes. To evaluate the effect of lncRNA Kcnq1ot1, siRNA and lentivirus-shRNA were synthesized to knockdown lncRNA Kcnq1ot1.
After ATO treatment, the Kcnq1ot1 and Kcnq1 expression levels were down regulated. lncRNA Kcnq1ot1 knockdown prolonged the action potential duration (APD) in vitro and exerted LQTS in vivo. Correspondingly, Kcnq1 expression was decreased after silencing lncRNA Kcnq1ot1. However, the knockdown of Kcnq1 exerted no effect on lncRNA Kcnq1ot1 expression.
To our knowledge, this report is the first to demonstrate that lncRNA Kcnq1ot1 downregulation is responsible for QT interval prolongation induced by ATO at least partially by repressing Kcnq1 expression. lncRNA Kcnq1ot1 has important pathophysiological functions in the heart and could become a novel antiarrhythmic target.
背景/目的：三氧化二砷（ATO）是一种已知的抗急性早幼粒细胞白血病（APL）药物，其临床应用受到严重心脏毒性和致命不良反应的限制，如长QT综合征（LQTS）导致的心源性猝死。ATO暴露导致心律失常的机制仍有待阐明。长链非编码RNA（lncRNAs）正在成为各种病理生理过程的主要调节因子。本研究旨在探讨lncRNAs在体内和体外ATO诱导的LQTS中的作用。
体内实验中，通过尾静脉给小鼠注射ATO。体外实验中，将ATO添加到原代培养的新生小鼠心肌细胞的培养基中。为了评估lncRNA Kcnq1ot1的作用，合成了siRNA和慢病毒-shRNA以敲低lncRNA Kcnq1ot1。
ATO处理后，Kcnq1ot1和Kcnq1表达水平下调。lncRNA Kcnq1ot1敲低在体外延长了动作电位时程（APD），并在体内诱发了LQTS。相应地，沉默lncRNA Kcnq1ot1后Kcnq1表达降低。然而，敲低Kcnq1对lncRNA Kcnq1ot1表达没有影响。
据我们所知，本报告首次证明lncRNA Kcnq1ot1下调至少部分通过抑制Kcnq1表达导致ATO诱导的QT间期延长。lncRNA Kcnq1ot1在心脏中具有重要的病理生理功能，可能成为一个新的抗心律失常靶点。
